10alpha-steroid-19-oic acid (19,11)-lactones, 19-carboxylic acid(19alpha, 11)-lactones and 11alpha, 19-dihydroxy-and 11alpha-hydroxy-19-hydroxymethyl-10alpha-androstenes



United States Patent C of Panama No Drawing. Filed Jan. 10, 1963, Ser. No. 250,481 18 Claims. (Cl. 260-239.57)

The present invention relates to novel cyclopentanophenanthrene derivatives and to a process for the production thereof.

More particularly the present invention relates to a novel process for the production of 10a-steroid-19-oic and l9-carboxylic acids, to their transformation into 19-hydroxy-10a-steroids, and to novel 11a,19-dihydroxy-10aandrostanes.

It has been disclosed in the literature that the changing of the configuration in the carbon 10 of the steroid molecule enhances certain activities and confers new properties to the steroids with this abnormal configuration. For example, the 10a,9,8-progesterone is several times more active than progesterone with respect to progestational and anti-estrogenic activities, as was disclosed in Belgian Patent No. 577,615, and 9a,10a-progesterone has also enhanced activities as was disclosed in Belgian Patent No. 577,616, neither of them having any androgenic effect.

In accordance with the present invention there has been discovered a new method for producing la-steroids from intermediates 10oc-Si6l0id-19-Oi0 and 19-carboxylic acids. The latter acids may be transformed into 10u,9B-steroids or into the corresponding 10a,l9-hydroxy steroids by conventional procedures.

The novel compounds of the present invention are represented by the following formula:

{$15 I (in In the above formula, X may be -OR or CH OR; R represents hydrogen or a hydrocarbon carboxylic acyl group of less than 12 carbon atoms; R represents hydrogen or a hydrocarbon carboxylic acyl group of less than 12 carbon atoms; and R represents hydrogen, lower alkyl, lower alkenyl, or lower alkinyl.

The acyl group is derived from hydrocarbon carboxylic acids containing less than 12 carbon atoms which may be saturated or unsaturated, of straight, branched, cyclic or cyclic-aliphatic chain, aromatic and may be substituted by functional groups such as hydroxy, alkoxy containing up to 5 carbon atoms, acyloxy containing up to 12 carbon atoms, nitro, amino or halogen. Typical ester groups are the acetate, propionate, enanthate, benzoate, trimethylacetate, t-butylacetate, phenoxyacetate, cyclopentylpropionate, aminoacetate, and ,G-chloropropionate.

The novel compounds of the present invention represented by the above formula are potent anabolic agents. In addition, they have anti-estrogenic, anti-gonadotrophic, anti-fibrillatory and appetite stimulating properties. Furthermore, they lower the blood cholesterol level, relieve premenstrual tension and suppress the output of the pituitary gland.

The novel process object of the present invention, by means of which there may also be produced the novel ice compounds represented by the above formula, is illustrated by the following scheme:

OR 0a In the above formulae R has the same meaning as heretofore; R represents hydroxyl, acyloxy, or acetyl; R represents hydrogen, a lower hydrocarbon residue, such as a lower alkyl, alkenyl or alkinyl group, a hydroxyl group or an acyloxy group; R represents hydrogen or a lower alkyl group; R and R together represent a dihydroxy acetone side-chain protected, preferably with a 17,20;- 20,21-bismethylenedioxy group; and Y represents an ethoxy group, or a halo-methyl group comprising a halogen atom of atomic weight larger than 19. The acyl groups are of the type described hereinabove.

In proceeding in accordance with the above equation, the starting compound (I), which is an 11ot-hydroxy-A -3 keto wot-steroid, preferably belonging to the androstene and pregnene series, and which may have a number of substituents in the molecule such as lower alkyl group in position 1, 2, 6, 7, l2, 14, 15, 16 and/ or 17; acyloxy groups in any of the indicated positions, and the like, is treated with ethyl chloroformate in the presence of pyridine, thus affording the corresponding llix-cathylate (II: Y=ethoxy) which is then treated with an alkali metal hydride under anhydrous conditions, for example with sodium hydride in dioxane-mineral oil, preferably at reflux temperature for a period of time of the order of 48 hours thus furnishing the corresponding 1Ooc-A St6rOid-1lot-Ol-3-OI1B-19-OiC acid (19,11)-lactone (III).

Alternatively, treatment of the starting steroid (I) with an anhydride or a chloride of a haloacetic acid, comprising a halogen atom of atomic weight larger than 19, such as chloroacetic acid or bromoacetic acid, in pyridine, affords the corresponding lla-haloacetate (II: Y=halomethyl) which is treated with an alkali metal hydride under anhydrous conditions, for example sodium hydride in dioxane-mineral oil, preferably at reflux temperature for a period of time of the order of 2 days thus furnishing the corresponding 101x-A Ster0id 11a-ol-3-one-19-carboxylic acid (l9u,l1)-lactone (V).

Reduction of the A -3-keto lactones (III, V) with lithium aluminum hydride affords the corresponding 3B,1lu,l9-trihydroxy or the corresponding 3B,11a-dihydroxy-19-hydroxymethyl-10a-A -steroids which upon selective oxidation of the 3fl-allylic hydroxyl group with approximately 1 molar equivalent of 2,3-dichloro-5,6- dicyano 1,4-benzoquinone, in dioxane, preferably at room temperature for approximately 3 hours yield the corresponding 11a,19-dihydroxy or 11a-hydr0xy-19-hydroxymethyl-a-A -steroid-3-ketones (IV, VI).

The compounds of the present invention having a secondary hydroxy group for example at 0- 11, or a primary hydroxyl, for example at C-19, are conventionally acylated in pyridine with a suitable acylating agent, such as a chloride or an anhydride of a hydrocarbon carboxylic acid of the type defined hereinbefore, thus affording the corresponding acylates.

The compounds of the present invention having in the molecule a tertiaryhydroxyl group, e.g. at C-17 are conventionally esterified in the present of p-toluenesulfonic acid with an acylating agent, such as acetic anhydride, caproic anhydride, cyclopentylpropionic anhydride or enanthic anhydride, to produce the corresponding esters.

The following specific examples serve to illustrate but are not intended to limit the scope of the present invention:

PREPARATION 1 1 It. of a sterilized aqueous medium containing 20 g. of peptone and 50 cc. of corn syrup was mixed with 30 cc.

of a growing culture of Rhizopus nigricans, prepared in the same medium by inoculation with a suspension rich in spores of such fungus which had been grown in agar, and the mixture was stirred for 24 hours, with aeration, at 28 C. At the end of this incubation period the pH of the culture was between 3.0 and 4.0 and, generally, the growth of the fungus was abundant.

A solution of 350 mg. of 19-nor-testosterone acetate in 33 cc. of ethanol was added to the culture thus obtained, and again stirred for 24 hours at 28 C., with aeration. .The incubation product was extracted several times with methylene dichloride, the extract was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, avoiding overheating.

The concentrated solution was chromatographed on silica and elution with mixtures chloroform-ether gave 11a-hydroxy-19-nor-testosterone 17-acetate.

V The compounds listed hereinafter under A, were treated according to the preceding procedure, thus furnishing the corresponding products set forth under B.

17a-methyl-IQ-nortestosterone 17a-ethinyl-l9-nortestosterone l9-nor-progesterone 17a-acotoxy-lQ-nor-progesterone 17,20;20,21-bismethylone-dioxy-19- nor-N-pregnen-B-one.

loa-methyl-l9-nor-progesterone 19-nor-A -androstene-3,17-dione- 17a-vinyl-19-nor-testosterone 11a-hydroxy-17a-methyl-l9-nortestosterone. 11a-hydroxy-17-rx-ethinyl-19-nortestosterone. 1lwhydroxy-l -norprogesterone. 11a-hydroxydh-aeetoxy-19-norprogesterone. 1la-hydroxy-l7,20;20,2l-bismethylenedioxy-19-n0rA 'pregnen-3- one. 1lot-hydroxy-lfia-rnethyl-lg-norprogesterone. 11a-hydroxy-19-nor-N-androsteno- 3, 1 7-dione 1lot-hydroxy-17a-vlnyl-l9-nortestosterone.

Example I 4 ate solution and water to neutral, then dried and evaporated to dryness. Crystallization of the residue from acetone-hexane afforded 11a-hydroxy-l9-nor-testosterone 11-cathylate-17-acetate (Cpd. No. 1).

Examplell A mixture of 1 g. of 11a-hydroxy-19-nor-testosterone l7-aoetate, 4 cc. of pyridine and 2 cc. of chloroacetyl chloride was kept at room temperature overnight, poured into ice water, the formed precipitate was filtered, washed with water and dried. Crystallization from acetonehexane gave 11a-hydroxy-l9-nor-testosterone-ll-chloroacetate-17-acetate (Cpd. No. 2).

Example Ill 11u-hydroxy-19-nor-testosterone-17-acetate was treated according to Example II, except that bromoacetyl chloride was used instead of chloroacetyl chloride, thus giving 1 1ot-hydroxy-19-nor-testosterone-1 1-br01noacetate-1-7- acetate (Cpd. No. 3).

Example IV 11a-hydroxy-l9-nor-testosterone' l7-acetate was treated in accordance with Example II, except that chloroacetyl chloride was substituted by iodo acetyl chloride, thus giving 11a hydro-xy-l9-nor-testosterone-11-iodoacetate-17- acetate (Cpd. No. 4).

Example V Example VI When treating compounds Nos. 2, 3, and 4 by the procedure described in Example III, there was obtained in each case a compound identical with IOa-A -androstene- 11a,17 3-diol-3-one-19-carboxylic acid (l9a,11) -lactone (Cpd. No. 6).

Example VII A solution of 1 g. of compound No. 5 in 50 cc. of tetra hydrofunan was added over a 30 minute period to a stirred suspension of 1 g. of lithium aluminum hydride in 50 cc. of anhydrous tetrahydrofuran. The mixture was refluxed for 2 hours, then cooled and cautiously treated with 5 cc. of ethyl acetate and 2 cc. of water. Solid sodium sulfate was added, the inorganic material filtered .off and thoroughly washed with hot ethyllacetate, the combined organic solutions upon evaporation yielded a crude material, which was purified by crystallization 'from acetone-hexane thus giving 10a-A -androstene-3fi,l1a,l7;3,19- tetrol (Cpd. No. 7).

Example VIII A mixture of g. of compound No. 7 in 20 cc. of dioxane, and 1.1 molar equivalents of 2,3-dichloro, 5,6-dicyano, 1,4-benzoquinone was kept at room temperature for 3 hours. The hydroqu-inone formed during the reaction was filtered off, and the filtrate evaporated to dryness. The residue was dissolved in acetone and filtered through 20 g. of almuina. Crystallization from acetone-hexane gave 10ot-A4 androstene 1la,l7,819 triol 3 one (Cpd.

Example IX The compounds listed hereinafter under A were treated according to Example I thus yielding respectively the corresponding compounds set forth under B.

A Cpd. B No.

110: hydroxy 17 methyl 19- 9 The ll-cathylate of Ila-hynor test0 sterone. droxy 17oz methyl 19 nortestosterone. 1102 hydroxy 17a vinyl 19- 10 The 11-cathylate of Ila-hynor-testo sterone. droxy 17a vinyl 19 nortestosterone. 11c: hydroxy 17a ethinyl 19- 11 The ll-cathylate of Ila-hynor-testosteroue. droxy 17oz cthinyl 19 -nortestosterone. 11a hydroxy 19 nor proges- 12 The eathylate of lla-hydroxyterone. l -nor-progesterone. 11a hydroxy 17a aeetoxy 19- 13 The cethylate of lla-hydroxynor-progesterone. 1701 acetoxy 19 nor progesterone. 11a hydroxy 16a methyl 19- 14 The cathylate o1 lla-hydroxynor-progesterone. 160: methyl 19 nor progesterone. 11a hydroxy 17,20;20,21 bis- 15 The ll-eathylate of lla-hymethylenedioxy 19 nor A droxy 17,20;20,21 bismethpregnen-3-one. ylenedioxy 19 nor A pregnen-3-one. 11oz hydroxy 19 nor A an- 16 The ll-eathylate of liq-hydrostene-3,17-dione. droxy 19 nor A androstene-3,17-dione.

Example X The starting compounds of Example IX were treated according to Example II thus yielding respectively:

Cpd. No.

17. 11a hydroxy 17oz methyl 19 nor testosterone ll-chloroacetate,

18. 110a hydroxy 17a vinyl 19 nor testosterone-1 l-chloroacetate,

19. 110'. hydroxy 17a ethinyl 19 nor testosterone-l l-chlonoacctate,

20. 11a hydroxy 19 nor progesterone chloroacetate,

21. 1100 hydroxy 17cc acetoxy 19 nor progesterone-chloroacetate,

22. 1101 hydroxy 16a methyl 19 nor progesterone-chlonoac'etate,

23. 110a hydroxy 17,20;20,21 bismethylenedioxy 19 nor A pregnen 3 one chloroacetate,

24. 11a hydroxy 19 nor A androstene 3,17

dione-chl-oroacetate.

Example XI The compounds Nos. 9 to 16, inclusive, were treated according to Example V, thus affording respectively:

Cpd. No.

25. 170: methyl 10cc A androstene 11a 176 diol-3-one-19-oic acid (19,11)-lactone.

26. 17a vinyl 10oz A androstene 1106,175

diol 3 one 19 oic acid (19,11)-lactone.

27. 1700 ethinyl 10oz A andr-ostene 11a,17,8

diol 3 one 19 oic acid (19,1l)-lactone 28. 10a A pregnen 11a ol 3,20 dione 19 oic acid (19,11)-lactone 29. 17cc acetoxy 101x A pregnen 11oz ol 3,20 d-ione 19 oic acid (19,11)-lactone 30. 16a methyl 10a A pregnen 11a o1 3,20 dione 19 oic acid (19,11) -1-actone 31. 17,20;20,21 bismethylenedioxy 10a A pregnen 11a -01 3 one 19 oic acid (19,11)-

lactone 1 32. 10cc A androsten 11a ol 3,17 dione 19 oic acid (19,11 )-lactone Example XII 33. 17a-methyl-10a-M-androstene-l1a,17(3-diol- 3-0ne-19-carboxylic acid (19a,11)-lactone 34. 17a-vinyl-10a-A -androstene-1101,1713-di01-3- one-19-carboxylic acid (19a, 11)-lactone 35. 17a-ethinyl-10u-A -androstene-11a,17B-diol-3- one-19-carboxylic acid (l9a,11)-lactone 36. IOa-M-pregnen-l1a-ol-3,20-dione-19- carboxylic-acid (19a,11)-lactone 37. 17 a-acetoxy-1Oa-A -pregnen-1 1a-ol-3,2()-dione- 19-carb0Xylic-acid (19a,11)-lactone 3 8. 16a-methyl- 1 Oa-M-pregnen-l 1 02-01-3 ,20-dione- 19-caro0xylic acid (19a,11)-lactone 39. 17,20; 20,21-bismethylenedioxy-10cx-A -pregnen- 11oc-ol-3-one-19-carboxylic acid (19a,11 )-lactone 40. 1Oa-A -androsten-1 loud-111111011649- carboxylic-acid (19a,1 l )-lactone Example XIII The compounds Nos. 25 to 32, inclusive, Were treated according to Example VII, thus yielding respectively:

Cpd. No.-

41. 17oc-methyl-10a-A -androstene-3B,1 111,175,19-

tetrol 42. 17a-vinyl-l0u-A -androstene-3fl,1111,175,19-

tetrol 43 17ix-et11iny1-1Oa-A -androstene-3 p, 1 1a, 1713, 1 9- tetrol 44. 10a-A -pregnene-3tL11a,19,2Ofl-tetrol 45. 1Ou-A -pregnene-35J 10c, 17a,19,20fi-pentol 47. 17,20;20,2l-bismethylenedioxy-10a-A -pregnene- 3fi,11a,19-triol 48. 10a-androstene-3fi,11a,17[3,19-tetrol Example XIV The compounds Nos. 33 to 40, inclusive, were treated according to Example VII, thus yielding respectively:

Cpd. No.

49. 19-hydroxymethyl-17u-methyl-loot-A androstene-3,B,11a,17;3-triol 50. 19-hydroxymethyl-17x-vinyl-10a-A -androstene- 3,B,l1a,17,8-triol 51. 19-hydroxymethyl-17oc-ethinyl-1(la-A androstene-3 13,1 1u,17fi-triol 52. 19-hydroxy1nethyl-10a-A -pregnene- 3 [1,1 10L,20fitrlO1 5 4. 19-hydroxymethyl-16a-methyl-10a-A -pregnene- 3B,171a,20fl-t1101 5 5 19-hydroxymethyl-17,20;20,21-bisrnethylenedioxy-10a-A -pregnene-3fl,1 lot-diol 5 6. 19-hydroxymethyl-10a-A -androstene- 3B,11o,17/3-triol Example XV The compounds Nos. 41 to 56, inclusive, were treated according to Example VIII, thus furnising respectively:

Cpd. No.

57. 17a-1nethyl-1Oa-A -androstene-11a,17[3,19-

triol-3-one 58. 17u-vinyl-1Oa-A -androstene-11a,17 6,19-

triol-3 -one 59. 17a-ethinyl-1Oa-A -androstene-1104,175,19-

t1'iol-3-one 60. 10a-A -pregnene-11a,19-20fi-triol-3 -one 61. 10u-A -pregnene-11a,17a,19,2O,8-tetrol-3-one 62. 16a-methyl-10a-A -pregnene-l10,19,2OB

triol-3-one 63. 17,20;20,2l-bismethylenedioxy-M1 pregnene-l1a,19-diol-3-one 64. 10a-A -androstene11a,17,8,19-triol-3-one 65. 19-hydroxymethyl-17(x-methyl-10a-A androstene-l1a,17/3-diol-3-one 66. l9-hydroxymethyl-17a-vinyllow-A androstene-l1a,17/3-diol-3 -one 67. 19-hydroxymethyl-l7a-ethiny1-1Oa-A androstene-11a,17fl-diol-3-one 68. 19-hydroxymethyl-l0a-A -pregnene-1la,20 8- diol-3-one 69. 19-hydroxymethyl-l0a-A -pregnenel1a,17a,20,8-triol-3-one 70. 19-hydroxymethyl-16a-methyl-ltlwM-pregnene- 11a,20B-diol-3-one 71. 19-hydroxymethyl-17,20;20,2l-bismethylenedioxy-10a-A -pregnene-1 1cc-Ol-3-Ol16 72. 19-hydroxyqmethyl-10a-A -androstene 1100,17fl-dil-3-0I1fi Example XVI A mixture of 1 g. of compound No. 8, 4 cc. of pyridine and 2 cc. of acetic anhydride was kept at room temperature overnight, poured into ice water, the formed precipitate was filtered, washed with water and dried. Crystallization from acetone-hexane gave 10a-A -androstene- 11a,l7fi,19-triol-3-one triacetate (Cpd. No. 73).

By the same procedure there were treated compounds Nos. 57, 58, 65 and 66, thus yielding respectively:

74. l7a-methyl-10a-A -androstene-l1a,17,8,19-

triol-3-one 11,19-diacetate,

75. 17a-vinyl-10a-A -androstene-11a,l7[3,19-

triol-3-one 11,19-diacetate,

76. l9-acetoxymethyl-17a-methy1-10a-A androstene-1 10:,17B-di0l-3-0I1fi ll-acetate,

77. 19-acetoxymethyl-17avinyl-10a-A androstene-11a,17p-diol-3-one ll-acetate,

Example XVII The starting compounds of Example XVI were treated following exactly the procedure described in that example, except that acetic anhydride was substituted by caproic anhydride, propionic anhydride, enanthic anhydride and cyclopentylpropionic anhydride thus affording respectively the corresponding caproates, propionates, enanthates and cyclopentylpropionates of said starting compounds.

Example XVIII To a solution of 5 g. of compound No. 57 in 100 cc. of anhydrous benzene there were added 1 g. of p-toluenesulfonic acid and cc. of caproic anhydride and the mixture was allowed to stand for 24 hours at room temperature, poured into ice and water, and the resulting mixture stirred to effect hydrolysis of the excess anhydride. The benzene layer was separated and washed with 10% sodium carbonate solution and water. Drying, evaporation and crystallization of the residue from etherhexane produced 17a-methyl-10a-A -androstene-11a,17,8, 19-triol-3-one tricaproate (Cpd. No. 7 8).

The compounds Nos. 58, 59, 65, 66 and 67 were treated according to the above procedure, thus yielding respectively:

Cpd. No.-

79. 17a vinyl 10a-A -androstene-11a,17fi,19-triol- 3-one tricaproate 80. 17a ethinyl-IOa-M-androstene-l1oz,17;8,19-triol- 3-one tricaproate 81. 19 caproxymethyl 17a methyl-10aA -androstene-11a,17B-diol-3-one dicaproate 82. 19 carpoxymethyl-l7a-vinyl-10a-A -androstene- 1la,17/3-diol-3-one dicaproate 83. 19-caproxymethyl 17a ethinyl-l0a-A -androstene-11a,17/3-diol-3-one dicaproate Example XIX Example XX The procedures of Examples V and VI were repeated except that potassium hydride was used instead of sodium hydride, thus giving exactly the same compounds.

Example XXI The procedure of Examples II and X were repeated, except that chloroacetyl chloride was substituted by chloro acetic anhydride thus affording identical results.

Example XXII The compound No. 6 was treated successively according to Examples VII and VIII thus furnishing respectively: 19-hydroxymethyl 10a A androstene-33,11a,17,8-triol (Cpd. No. 84), and 19-hydroxymethyl-IOa-M-androstene- 1la,17,8-diol-3-one (Cpd. No. 85).

I claim:

1. A compound of the following formula:

if (all an wherein X is selected from the group consisting of -OR and CH OR; R is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms; R is a member of the group consisting of hydrogen and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms; and R is selected from the group consisting of hydrogen, a lower alkyl group, a lower alkenyl group and a lower alkinyl group.

2. 10a-A -androstene-l1a,17,8,19-triol-3-one.

3. 17a methyl 10a-A -androstene-11a,17fl,19-triol-3- one.

4. 17a-vinyl-10a A androstene-lla,l7fi,19-triol-3- .one.

5. 17a-ethinyl-10a A androstene-1la,17fi,19-triol-3- one.

6. 19 hydroxymethyl-10a-A -androstene-11a,l7,B-diol- 3-one.

7. 19-hydroxymethyl 17a methyl-10a-A -androstene- 11a,17,8-diol-3-one.

8. 19 hydroxymethyl 17a vinyl-l0a-A -androstene- 11oc,17,B-di0l-3O1l8.

9. 19-hydroxymethyl 17a ethinyl-lOa-A androstene- 1la,l7/3-diol-3-one.

10'. A process for the preparation of a steroid selected from the group consisting of 1Oa-A -11a-ol-3-one-19-oic acid (19,11)-lactones of the androstene and pregnene series which comprises treating the corresponding llahydroxy-M 3 keto-l9-nor-steroid ll-cathylate with an alkali metal hydride under anhydrous conditions.

11. A process according to claim 10 wherein said alkali metal hydride is sodium hydride.

12. A process for the preparation of a steroid selected from the group consisting of 10a-A -1la-ol-3-one-19-oic acid (19,11)-lactones of the androstene and pregnene series which comprises treating the corresponding 11ahydroxy-A -3-keto-19-nor-steroid with ethyl chloroformate in the presence of pyridine to form the corresponding 11a-hydroxy-A -3-keto 19 nor-steroid ll-cathylate, and treating said cathylate with an alkali metal hydride under anhydrous conditions to form said lactone.

13. A process according to claim 12 wherein said alkali metal hydride is sodium hydride. i

14. A process for the preparation of a steroid selected from the group consisting of lOa-M-lla-o1-3-one-19-carboxylic acid (19a,11)-lactones of the androstene and pregnene series which comprises treating the corresponding 11a-hydroxy-A -3-keto 19 nor steroid ll-haloacetate, where-in the halogen atom has an atomic weight greater than 19, with an alkali metal hydride under anhydrous conditions.

15. A process according to claim 14 wherein said alkali metal hydride is sodium hydride and said haloacetate is the chloroacetate.

16. A process for the preparation of a steroid selected from the group consisting of 10u-A -11a-ol-3-one-19-carboxylic acid (19a,l 1)-1actones of the androstene and pregnene series which comprises treating the corresponding 11a-hydroxy-A -3-keto 19 nor steroid with a reagent selected from the group consisting of chlorides and anhydrides of haloacetic acids wherein the halogen atom has an atomic weight greater than 19, in the presence of 1G pyridine, to form the corresponding 11o-hydroXy-A -3- keto-19-nor-steroid ll-haloacetate, and treating said haloacetate with an alkali metal hydride under anhydrous conditions to form said lactone.

17. A process according to claim 16 wherein said reagent is chloroacetyl chloride and said alkali metal hydride is sodium hydride.

18. A process according to claim 16 wherein said reagent is chloroacetic anhydride and said alkali metal hydride is sodium hydride.

Eppstein et al Dec. 16, 1958 Wettstein et a1. Feb. 5, 1963 

1. A COMPOUND OF THE FOLLOWING FORMULA:
 12. A PROCESS FOR THE PREPARATION OF A STEROID SELETCED FROM THE GROUP CONSISTING OF 10$4-11-A-OL-3-ONE 19-OIC ACID (19,11)-LACTONES OF THE ANDROSTENE AND PREGNENE SERIES WHICH COMPRISES TREATING THE CORRESPONDING 11 AHYDROXY $4-3-KETO-19-NOR-STEROID WITH ETHYL CHOLORFORMATE IN THE PRESENCE OF PYRIDINE TO FROM THE CORRESPONDING 11 A-HYDROXY $4-3-19- NOR-STEROID 11-CATHYLATE, AND TREATING SAID CATHYLATE WITH AN ALKALI METAL HYDRIDE UNDER ANHYDROUS CONDITIONS TO FORM SAID LACTONE. 